Olaparib (AZD-2281, trade name Lynparza) is an FDA-approved targeted therapy for cancer, developed by KuDOS Pharmaceuticals and later by AstraZeneca. Lynparza is approved in the form of 50 mg capsules. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers. In December 2014, Olaparib was approved for use as a single agent by the EMA and the FDA. The FDA approval is in for germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy. The prescribing information instructs physicians to “select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations.”
AstraZeneca recently announced that FDA has granted Breakthrough Therapy Designation (BTD) for the oral poly ADP-ribose polymerase (PARP) inhibitor Lynparza™ (olaparib), for the monotherapy treatment of BRCA1/2 or ATM gene mutated metastatic Castration Resistant Prostate Cancer (mCRPC) in patients who have received a prior taxane-based chemotherapy and at least one newer hormonal agent (abiraterone or enzalutamide).
Given the great usefulness of this compound, a need in the art exists to effectively and efficiently synthesize olaparib.
A key intermediate in the process of preparing olaparib is 2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl)methyl)-benzoic acid (compound D). Two synthetic approaches of olaparib are the main design developed by this company and they are disclosed or claimed in the U.S. Pat. Nos. 7,449,464, 7,692,006 and 8,247,416. Scheme 1, below, illustrates the synthetic schemes describes in these patents.

The '006 approach involves contacting compound D with 1-Boc-piperazine in dimethylacetamine (DMA) in the presence of HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) to provide 4-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoyl]-piperazin-1-carboxylic acid tert-butyl ester (compound C), followed by adding concentrated HCl to remove tert-butoxycarbonyl (Boc) group and obtaining 4-[4-fluoro-3-(piperazine-1-carbonyl)benzyl]-2H-phthalazin-1-one (compound B), and then compound B couples with cyclopropane carbonyl chloride to afford crude 4-[3-(4-cyclocarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (i.e., crude olaparib).
The '416 approach is related to a direct coupling reaction of compound D with 1-(cyclopropylcarbonyl)piperazine (compound I) or 1-(cyclopropylcarbonyl)piperazine HCl salt (compound I′) in the presence of HBTU to obtain crude olaparib (Scheme 1).
According to the above-mentioned '006 approach, treatment of compound D with 1-Boc-piperazine in dimethylacetamide (DMA) in the presence of an expensive (and difficult to dissolve) amide coupling reagent 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) resulted in the formation of compound C with only a 78% yield.                See, Scheme 2.        

In the next step of the '006 approach, compound C underwent de-Boc reaction under acidic conditions (concentrated HCl(aq) in MeOH) to afford compound B with a yield of only 58.50% yield. See, Scheme 3.

Subsequently, a pre-mixed solution of triethylamine (Et3N) and cyclopropane carbonyl chloride in dichloromethane was added dropwise to a stirred solution of compound B in dichloromethane. Upon completion, the reaction mixture was extracted with 5% citric acid(aq), 5% Na2CO3(aq), and water, followed by distilling dichloromethane and replacing the distillate with ethanol. The resulting mixture was filtered and the solid was recrystallized in water to afford olaparib in 90% yield. See, Scheme 4. However, this reaction includes the use of toxic chemicals such as dichloromethane and requires distilling the solvent in the work up steps.

According to the '416 approach, treatment of compound D with 1-(cyclopropylcarbonyl)piperazine or its mineral acid salt in the presence of an amide coupling reagent 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and a base in acetonitrile led to the formation of olaparib directly. See, Scheme 5. However, the process described in the '416 patent only affords olaparib in 84% or 62% yields after recrystallization. Moreover, this reaction includes the use of an expensive (and difficult to dissolve) coupling agent (HBTU) as well as a toxic and highly flammable solvent in acetonitrile.

In view of the foregoing, the need exists for an improved process to produce olaparib with commercially acceptable yields, increased efficiency, and less toxic chemicals.